The pathogenesis and promotion of tumors were studied using a mouse and rat liver initiation-promotion system, a nitrosomethylurea (NMU-induced thyroid tumor system in rats, skin painting studies in mice, and an aged F344 rat liver model system. Tumor promotion can be an irreversible biological process which may require only a short period of exposure to the promoter for effective tumor promotion. For example, in the initiated skin of Sencar mice after only two exposures to 12-0-tetradecanoylphorbol-13-acetate (TPA), effective skin tumor promotion was seen. Tumors promoted after only short-term exposure to TPA grew progressively and did not regress after exposure to TPA was terminated. In the thyroid gland, withdrawal of a goitrogenic iodine-deficient diet at various time periods after exposure to NMU allowed some of the promoted proliferative lesions to progress to large tumors. In mouse liver, the tumor promoter di(2-ethylhexyl)phthalate (DEHP) was effective as a tumor promoter after only 28 days of exposure while phenobarbital (PB) was only effective after continuous exposure. DEHP was found to promote the development of liver tumors in mice but not in rats although it is a complete carcinogen for the liver in both species. DEHP caused liver enlargement, hyperplasia, and peroxisomal proliferation in both species; these processes thus cannot be sufficient as possible mechanisms for tumor promotion in this system. Aged F344 rats, which have naturally occurring gamma-glutamyl transpeptidase (GGT)-negative focal proliferative basophilic hepatocellular lesions in their livers, were given PB in their water to determine the role of the promoter on these naturally occurring foci. PB was found to induce focal eosinophilic GGT-positive, hepatocelluar foci de novo and not to promote the growth or increase the incidence of the naturally occurring basophilic foci.